1. Field of the Invention
The invention relates to compositions and a process for the manufacture of a flavanolignan-containing substance from milk thistle displaying enhanced aqueous solubility relative to pure flavanolignan preparations. The substance of the method according to the invention is useful for the manufacture of solid medicinal products and dietary supplements with desired improved dissolution characteristics.
2. Summary of the Related Art
Fruits of milk thistle (Silybum marianum (L.) Gaertn.) contain several isomeric compounds of flavanol-lignane type of the general formula C25H22O11-silybinin A, silybinin B, isosilybinin A, isosilybinin B, silydianin and silychristin—collectively called flavanolignans of milk thistle or silymarin. Silymarin (generally available as the dry extract of milk thistle) has been reported to have numerous pharmacological activities such as for example, antioxidant effect, stabilization of cell membranes, and stimulation of biosynthesis of proteins to mention a few. Silybin (a mixture of silybinin A and silybinin B) has been found to be particularly suited as an hepatoprotective agent. Silymalin is effective in the treatment and prophylaxis of liver disease including acute and chronic intoxication of the liver caused by toxins, (including drugs and various alcohols, e.g., carbon tetrachloride, galactosamine, paracetamol, ethanol, phalloidin and α-amanitin). Silymarin is an active component of pharmaceutical products, (e.g., LEGALON®, Madus AG, Koln, Germany; Hepamarin, Pharmasan GmbH, Freiburg, Germany; HEPADURAN®, Zwinkscher GmbH, Karlsruhe, Germany; or SILYHEXAL®, Hexal Pharma AG, Wien, Austria) used to treat and prevent hepatic diseases. More information about silymarin and its use can be found in Morazzoni et al., Fitoterapia, LXVI, 3-42, (1995); Sailer et al., Drugs, 61: 2035-2063, (2001); Wellington et al., BioDrugs, 15(7): 465-489, (2001).
The silymarin preparation used for manufacture of pharmaceutical preparations or food supplements is thus a purified extract standardized to include specific flavanolignans. Pharm. Forum 28: 418-420, (2002) provides that silymarin contains not less than 90% and not more than 110% of silymarin, calculated as silybin on the dried basis; consisting of not less than 20.0% and not more than 45.0% of the sum of silydianin and silycristin; not less than 40% and not more than 65% for the sum of silibin A and silibin B; and not less 10.0% and not more than 20% for the sum of isosilybin A and isosilybin B; contains from about 40 up to 80% flavanolignans consisting of from about 40 up to 65% of the sum of silybinin A and B; from about 20 up to 45% of the sum of silychristin and silydianin and from about 10 up to 20% of the sum of isosilybinin A and B.
However, the use of milk thistle flavanolignans in general and that of silymarin and its components in the preparation of pharmaceutical products is greatly impaired by the low solubility in both hydrophilic and lipophilic environments of these compounds which greatly reduces their bioavailability and resorbability in mammals. Given the tremendous therapeutic potential, it is not surprising that several investigators have sought a variety of approaches to address the solubility/bioavailability problems as attested by the large body of literature on point including several patents discussed hereinafter.
One approach lies in the preparation of silybin esters (mixture of silybinins A and B, possibly also isosilybinins A and B) with dicarboxylic acid. For example U.S. Pat. Nos. 4,895,839 and 5,196,448 describe a di-sodium salt of bis-hemisuccinate of silybin. This preparation is presently incorporated in in LEGALON® SIL inj., a pharmaceutical product for the treatment of serious poisoning by Amanita mushrooms or other hepatotoxic compounds, marketed by Madaus &Co.
Another approach has been the preparation of silybin glycosides as set forth for example in CZ Patent No. 287 657. The described silybin glycosides are more soluble in water than silybin and they show similar effects as silymarin. Complex compounds of silymarin or silybin with phospholipides are also described by U.S. Pat. Nos. 4,764,508 and 4,895,839. These complexes are prepared by dissolution of components (1 mol of silymarin or silybin and 0.3 up to 2.0 mol of phosphatidyl choline, phosphatidyl serine or phosphatidyl ethanolamine) in aprotic solvent (dioxane or acetone) and by precipitation of the complex by addition of aliphatic hydrocarbon or lyophilization or spray drying. The described complex compounds are the basis of the substance called SILIPED™ or SILYPHOS™, (manufactured by Indena) currently under clinical trials (Comoglio A., et al., Biochem. Pharmacol., 50:(8):1313-1316 (1995).
Yet another approach has been formulation in cyclodextrin complexes notorious for their role in solubilizing a variety of compounds. Inclusion complexes of silybinin with cyclodextrines are described in the U.S. Pat. No. 5,198,430. Complexes of silybinin are described with α-, β- and γ-cyclodextrine and their derivatives in molecular ratio of 1 mol of silybinin with 1 up to 4 mol of the corresponding cyclodextrine. Complexes are prepared by dissolution of both components in aqueous ammonia and by removal of the ammonia either by evaporation or neutralization with hydrochloric acid and by subsequent drying or lyophilization.
Solutions of silymarin in polyethylene glycol alone or in polyethylene glycol and some co-solvents and/or surfactants are described in WO 99/18985. The gelatin capsules filled with such solutions show higher solubility in dissolution tests than silymarin alone.
Another patented procedure for increasing the biological availability of silymarin consists in the preparation of coprecipitates of flavanolignans with carriers and detergents (see for example, U.S. Pat. No. 5,906,991 and EP 722719). Suitable carriers according to these methods include water soluble saccharides, derivatives of cellulose and polyvinylpyrrolidone whereas polysorbates of fatty acids are used as detergent. These coprecipitates are said to have higher solubility properties as compared to untreated silymarin. However, some of these obligatory carriers and excipients according to these patents coprecipitate as contaminants with the flavanolignans. Unfortunately, some of these contaminants are known toxic compounds and thus may produce adverse reactions in a patient further exacerbating an already existing condition.
Thus, the currently available approaches for the preparation of flavanolignan compositions suffer from a number of drawbacks. In general, conventional methodologies fail to produce a sufficiently soluble preparation. Moreover, because of the low solubility, such preparations are not sufficiently bioavailable. A further disadvantage of the formulations in presently the art is that often the flavanolignan is bound to a chemical compound which can physiologically act as a foreign substance in the body thereby bringing about undesired side reactions or impair the effectiveness of the flavanolignan. Therefore, there remains a need to identify and develop improved methodologies and compositions. Such methodologies and compositions should overcome the shortcomings of the traditional methods in the literature. It is an object of the present invention to provide flavanolignan preparations which reduce the binding of the flavanolignans to foreign compounds and possess high rate of liberation wherein the liberation is accomplished physically by means of destruction of its crystalline lattice (amorphous substance). These flavanoligaans preparations should maintain their efficacy while limiting their binding to foreign compounds.